Treatment of, and differential diagnosis between, acth-dependent cushing's syndrome and acth-independent cushing's syndrome

Abstract

Methods for treating and differential diagnosis between ACTH-Dependent and ACTH-Independent Cushing's syndrome are disclosed, in which a glucocorticoid receptor antagonist (GRA) is administered to a Cushing's syndrome patient with a basal ACTH level less than about 25 pg/mL. If i) the patients blood ACTH and ii) the patients blood cortisol, or adrenal hormone, or adrenal pre-hormone levels rise, or if the ACTH:cortisol ratio increases, then ACTH-Dependent Cushing's syndrome is diagnosed. If those levels do not rise, or if the ACTH:cortisol ratio decreases, then ACTH-Independent Cushing's syndrome is diagnosed. In some instances, the patient is recovering from surgery to remove an ACTH secreting tumor, and the method described herein is used to determine if the tumor resection was successful or complete. The GRA may be mifepristone, or a non-steroidal GRA having a heteroaryl-ketone fused azadecalin backbone, an octahydro fused azadecalin backbone, a cyclohexyl pyrimidine backbone, or a fused azadecalin backbone.

1 . A method of treating Cushing's syndrome in a patient and differentially diagnosing between adrenocorticotropin hormone (ACTH)-Dependent Cushing's syndrome and ACTH-Independent Cushing's syndrome, the method comprising:
 (a) selecting a patient having Cushing's syndrome, having a basal level of plasma or serum cortisol, and having a detectable basal level of plasma or serum ACTH that is less than or equal to about 25 picograms per milliliter (pg/mL);   (b) administering to the patient at least one dose of a glucocorticoid receptor antagonist (GRA);   (c) measuring the level of ACTH or cortisol in a sample obtained from the patient after GRA administration; and   (d) determining that the patient has ACTH-Dependent Cushing's syndrome if, after said GRA administration, the patient's ACTH levels rise or the patient's cortisol levels rise as compared to their respective basal levels; or   (e) determining that the patient has ACTH-Independent Cushing's syndrome if, after said GRA administration, neither the patient's ACTH level nor the patient's cortisol level rises as compared to their respective basal levels,   Whereby Cushing's syndrome is treated and differential diagnosis between a) ACTH-Dependent Cushing's syndrome and between b) ACTH-Independent Cushing's syndrome is obtained.   
     
     
         2 . The method of  claim 1 , wherein the basal level of ACTH is between about 5 pg/mL to about 25 pg/mL. 
     
     
         3 . The method of  claim 1 , wherein the level of ACTH, cortisol, or both is measured 2 to 24 hours after GRA administration. 
     
     
         4 . The method of  claim 1 , wherein the patient has undergone surgery to remove an adrenocorticotrophic hormone (ACTH) secreting tumor. 
     
     
         5 . The method of  claim 4 , wherein the tumor is a pituitary ACTH secreting tumor. 
     
     
         6 . The method of  claim 4 , wherein the tumor is an ectopic ACTH secreting tumor. 
     
     
         7 . The method of  claim 1 , wherein the GRA is administered orally. 
     
     
         8 . The method of  claim 1 , wherein the glucocorticoid receptor antagonist is mifepristone. 
     
     
         9 . The method of  claim 1 , wherein the glucocorticoid receptor antagonist comprises a non-steroidal backbone selected from a cyclohexyl pyrimidine backbone, a fused azadecalin backbone, a heteroaryl-ketone fused azadecalin backbone, and an octahydro fused azadecalin backbone. 
     
     
         10 . The method of  claim 9 , wherein the glucocorticoid receptor antagonist is selected from the cyclohexyl pyrimidine compound (E)-6-(4-Phenylcyclohexyl)-5-(3-trifluoromethylbenzyl)-1H-pyrimidine-2,4-dione, which has the structure: 
       
         
           
           
               
               
           
         
       
       the fused azadecalin compound (R)-4-a-ethoxymethyl-1-(4-fluoro-phenyl)-6-(4-trifluoromethyl-benzene sulfonyl)-4,4a,5,6,7,8-hexahydro-1H,1,2,6-triaza-cyclopenta[b]naphthalene, which has the structure: 
       
         
           
           
               
               
           
         
       
       the heteroaryl-ketone fused azadecalin compound (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyppyridin-2-yl)methanone, which has the following structure: 
       
         
           
           
               
               
           
         
         the heteroaryl-ketone fused azadecalin compound (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,-7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone, which has the following structure: 
       
       
         
           
           
               
               
           
         
       
       the heteroaryl-ketone fused azadecalin compound (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl) sulfonyl)-4,4a, 5,6,7,8-hexahydro-1-H-pyrazolo P,4-g]isoquinolin-4a-yl) (pyridin-2-yl)methanone, which has the following structure: 
       
         
           
           
               
               
           
         
       
       and the octahydro fused azadecalin compound ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo [3,4-g] isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, which has the structure: 
       
         
           
           
               
               
           
         
       
     
     
         11 - 21 . (canceled) 
     
     
         22 . A method of treating Cushing's syndrome in a patient and differentially diagnosing between adrenocorticotropin hormone (ACTH)-Dependent Cushing's syndrome and ACTH-Independent Cushing's syndrome, the method comprising:
 (a) selecting a patient having Cushing's syndrome, having a basal level of plasma or serum cortisol, and having a detectable basal level of plasma or serum ACTH that is less than or equal to about 25 picograms per milliliter (pg/mL);   (b) determining a basal ACTH:cortisol ratio by dividing the numerical value of the basal ACTH level by the numerical value of the basal cortisol level;   (c) administering to the patient at least one dose of a glucocorticoid receptor antagonist (GRA);   (d) measuring the level of ACTH and the level of cortisol in a sample obtained from the patient after GRA administration;   (e) determining an after-GRA ACTH:cortisol ratio by dividing the numerical value of the ACTH level measured after GRA administration by the numerical value of the cortisol level measured after GRA administration;   and   differentially diagnosing between adrenocorticotropin hormone (ACTH)-Dependent Cushing's syndrome and ACTH-Independent Cushing's syndrome by comparing said basal ACTH:cortisol ratio to said after-GRA ACTH:cortisol ratio, wherein   if the basal ACTH:cortisol ratio is greater than the after-GRA ACTH:cortisol ratio, then the patient is diagnosed with ACTH-independent Cushing's syndrome; and   if the basal ACTH:cortisol ratio is smaller than the after-GRA ACTH:cortisol ratio, then the patient is diagnosed with ACTH-dependent Cushing's syndrome,   Whereby Cushing's syndrome is treated and differential diagnosis between a) ACTH-Dependent Cushing's syndrome and between b) ACTH-Independent Cushing's syndrome is obtained.   
     
     
         23 . The method of  claim 22 , wherein the change in ACTH:cortisol ratio from before GRA treatment to after GRA treatment is at least about 5% of the value of the basal ACTH:cortisol ratio. 
     
     
         24 - 25 . (canceled) 
     
     
         26 . The method of  claim 22 , wherein the change in ACTH:cortisol ratio from before GRA treatment to after GRA treatment is at least about 20% of the value of the basal ACTH:cortisol ratio. 
     
     
         27 . The method of  claim 22 , wherein the change in ACTH:cortisol ratio from before GRA treatment to after GRA treatment is greater than about 25% of the value of the basal ACTH:cortisol ratio. 
     
     
         28 . The method of  claim 22 , wherein the basal level of ACTH is between about 5 pg/mL to about 25 pg/mL. 
     
     
         29 . The method of  claim 22 , wherein the level of ACTH, cortisol, or both is measured 2 to 24 hours after GRA administration. 
     
     
         30 - 32 . (canceled) 
     
     
         33 . The method of  claim 22 , wherein the GRA is administered orally. 
     
     
         34 . The method of  claim 22 , wherein the glucocorticoid receptor antagonist is mifepristone. 
     
     
         35 . The method of  claim 22 , wherein the glucocorticoid receptor antagonist comprises a non-steroidal backbone selected from a cyclohexyl pyrimidine backbone, a fused azadecalin backbone, a heteroaryl-ketone fused azadecalin backbone, and an octahydro fused azadecalin backbone. 
     
     
         36 . The method of  claim 35 , wherein the glucocorticoid receptor antagonist is selected from the cyclohexyl pyrimidine compound (E)-6-(4-Phenylcyclohexyl)-5-(3-trifluoromethylbenzyl)-1H-pyrimidine-2,4-dione, which has the structure: 
       
         
           
           
               
               
           
         
       
       the fused azadecalin compound (R)-4-a-ethoxymethyl-1-(4-fluoro-phenyl)-6-(4-trifluoromethyl-benzenesulfonyl)-4,4a,5,6,7,8-hexahydro-1H,1,2,6-triaza-cyclopenta[b]naphthalene, which has the structure: 
       
         
           
           
               
               
           
         
       
       the heteroaryl-ketone fused azadecalin compound (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyppyridin-2-yl)methanone, which has the following structure: 
       
         
           
           
               
               
           
         
         the heteroaryl-ketone fused azadecalin compound (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,-7,8-hexahydro-1H-pyrazolo [3,4-g] isoquinolin-4a-yl)(thiazol-2-yl)methanone, which has the following structure: 
       
       
         
           
           
               
               
           
         
       
       the heteroaryl-ketone fused azadecalin compound (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1-H-pyrazolo P,4-glisoquinolin-4a-yl) (pyridin-2-yl)methanone, which has the following structure: 
       
         
           
           
               
               
           
         
       
       and the octahydro fused azadecalin compound ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, which has the structure: 
       
         
           
           
               
               
           
         
       
     
     
         37 - 45 . (canceled)